SUMMARY In this Phase IIB proposal, we seek funding to complete the IND-enabling development of CF-404, a mixture of three native human monoclonal antibodies (mAbs). Activity has been established in mouse models against representatives of all major circulating strains of influenza A and B. By providing a pan-influenza treatment, we avoid delays associated with strain typing, with improved outcomes expected from the prompt treatment. We specifically propose here to address regulatory issues relating to delivery of the mAb mixture by inhalation. Our background work demonstrated that inhaled delivery provides superior efficacy compared to systemic delivery, at ~10-fold lower dose. The inhalation technology from industry leader Aerogen Pharma is established as suitable for hospitalized patients, including those on a ventilator. Due to drug resistance to the existing influenza therapeutic drugs, there is a high need for our product. The first class of small molecule therapeutics, the amantadines, are now largely useless due to drug resistance. The second class, neuraminidase inhibitors, are currently experiencing similar emergence of resistance. The newest class, polymerase inhibitors, has already shown worrisome signs of early emergence of drug resistant strains (10% in the Phase 3 trials). By contrast, intensive selection in vitro for virus that escapes our mAbs has shown that resistance is likely to be far less common than for the small molecule antivirals. The impact of CF-404 is thus expected to be high.